DISP1 deficiency: monoallelic and biallelic variants cause a spectrum of midline craniofacial malformations
Alinoë Lavillaureix
(1)
,
Paul Rollier
(1)
,
Artem Kim
(2, 3)
,
Veranika Panasenkava
(2)
,
Marie de Tayrac
(1, 2)
,
Wilfrid Carré
(1)
,
Helene Guyodo
(2)
,
Marie Faoucher
(1)
,
Elisabeth Poirel
(1)
,
Linda Akloul
(1)
,
Chloé Quélin
(1)
,
Sandra Whalen
,
Jessica Bos
(4)
,
Marjoleine Broekema
(4)
,
Johanna M. van Hagen
(4)
,
Katheryn Grand
(5)
,
Michelle Allen-Sharpley
(5)
,
Emily Magness
(6)
,
Scott Mclean
(6)
,
Hulya Kayserili
,
Umut Altunoglu
,
Angie En Qi Chong
(7)
,
Shifeng Xue
(7)
,
Médéric Jeanne
(8)
,
Naif Almontashiri
(9)
,
Wisam Habhab
(10)
,
Clémence Vanlerberghe
(11)
,
Laurence Faivre
(12)
,
Eléonore Viora-Dupont
(12)
,
Christophe Philippe
(12)
,
Hana Safraou
(12)
,
Fanny Laffargue
,
Luisa Mittendorf
,
Rami Abou Jamra
(13)
,
Siddaramappa Jagdish Patil
,
Ashwin Dalal
(14)
,
Asodu Sandeep Sarma
(14)
,
Boris Keren
,
Bruno Reversade
(15)
,
Christèle Dubourg
(1, 2)
,
Sylvie Odent
(1, 2)
,
Valérie Dupé
(2)
1
Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
2 IGDR - Institut de Génétique et Développement de Rennes
3 USC - University of Southern California
4 Amsterdam UMC - Amsterdam University Medical Centers
5 Cedars-Sinai Medical Center
6 BCM - Baylor College of Medicine
7 NUS - National University of Singapore
8 UMR U 1253
9 Taibah University
10 King Abdulaziz University
11 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
12 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
13 Institute of Human Genetics [Cologne]
14 CDFD - Centre for DNA Fingerprinting and Diagnostics [Hyderabad]
15 A*STAR - Agency for science, technology and research [Singapore]
2 IGDR - Institut de Génétique et Développement de Rennes
3 USC - University of Southern California
4 Amsterdam UMC - Amsterdam University Medical Centers
5 Cedars-Sinai Medical Center
6 BCM - Baylor College of Medicine
7 NUS - National University of Singapore
8 UMR U 1253
9 Taibah University
10 King Abdulaziz University
11 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
12 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
13 Institute of Human Genetics [Cologne]
14 CDFD - Centre for DNA Fingerprinting and Diagnostics [Hyderabad]
15 A*STAR - Agency for science, technology and research [Singapore]
Alinoë Lavillaureix
- Fonction : Auteur
- PersonId : 1192596
- ORCID : 0000-0002-3727-9530
Paul Rollier
- Fonction : Auteur
- PersonId : 1271347
- IdHAL : paul-jg-rollier
Wilfrid Carré
- Fonction : Auteur
- PersonId : 834354
Chloé Quélin
- Fonction : Auteur
- PersonId : 917957
Sandra Whalen
- Fonction : Auteur
- PersonId : 760399
- ORCID : 0000-0001-9156-5047
Scott Mclean
- Fonction : Auteur
- PersonId : 1345881
- ORCID : 0000-0002-7269-5847
Hulya Kayserili
- Fonction : Auteur
- PersonId : 1351633
- ORCID : 0000-0003-0376-499X
Umut Altunoglu
- Fonction : Auteur
Shifeng Xue
- Fonction : Auteur
- PersonId : 784484
- ORCID : 0000-0002-4668-5952
Clémence Vanlerberghe
- Fonction : Auteur
- PersonId : 1276261
- ORCID : 0000-0003-3884-2054
Christophe Philippe
- Fonction : Auteur
- PersonId : 761163
- IdRef : 083945237
Fanny Laffargue
- Fonction : Auteur
Luisa Mittendorf
- Fonction : Auteur
Rami Abou Jamra
- Fonction : Auteur
- PersonId : 1261806
- ORCID : 0000-0002-1542-1399
Siddaramappa Jagdish Patil
- Fonction : Auteur
Boris Keren
- Fonction : Auteur
- PersonId : 1100999
Bruno Reversade
- Fonction : Auteur
- PersonId : 758347
- ORCID : 0000-0002-4070-7997
- IdRef : 109134621
Christèle Dubourg
- Fonction : Auteur
- PersonId : 1202229
- ORCID : 0000-0003-1345-4522
Valérie Dupé
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 851455
- ORCID : 0000-0003-4859-0612
Connectez-vous pour contacter l'auteur
Résumé
PURPOSE: DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog (SHH), a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better delineate the clinical phenotypes associated with DISP1 variants. METHODS: This study was based on the identification of at least one pathogenic variant of the DISP1 gene in individuals for whom detailed clinical data were available. RESULTS: A total of 23 DISP1 variants were identified in heterozygous, compound heterozygous or homozygous states in 25 individuals with midline craniofacial defects. Most cases were minor forms of HPE, with craniofacial features such as orofacial cleft, solitary median maxillary central incisor (SMMCI), and congenital nasal pyriform aperture stenosis (CNPAS). These individuals had either monoallelic loss-of-function variants or biallelic missense variants in DISP1. In individuals with severe HPE, the DISP1 variants were commonly found associated with a variant in another HPE-linked gene (i.e. oligogenic inheritance). CONCLUSION: The genetic findings we have acquired demonstrate a significant involvement of DISP1 variants in the phenotypic spectrum of midline defects. This underlines its importance as a crucial element in the efficient secretion of SHH. We also demonstrated that the very rare SMMCI-CNPAS combination is part of the DISP1-related phenotype. The present study highlights the clinical risks to be flagged up during genetic counseling after the discovery of a pathogenic DISP1 variant.